Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]12([CH2:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[OH:19][C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26]Br)=[CH:22][CH:21]=1>>[C:2]12([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([CH2:26][CH2:25][O:24][C:23]4[CH:28]=[CH:29][C:20]([OH:19])=[CH:21][CH:22]=4)[CH2:15][CH2:14]3)[CH2:11][CH:6]3[CH2:5][CH:4]([CH2:10][CH:8]([CH2:7]3)[CH2:9]1)[CH2:3]2
Reactant: Oc1ccc(OCCBr)cc1
Reactant: C1CC(CC23CC4CC(CC(C4)C2)C3)CCN1
Agent: Cl
Product: Oc1ccc(OCCN2CCC(CC34CC5CC(CC(C5)C3)C4)CC2)cc1

Procedure:
b)The title compound was prepared from 4-(1-adamantylmethyl)piperidine hydrochloride (350 mg, 1.30 mmol) and 2-(4-hydroxyphenoxy)ethyl bromide (295 mg, 1.36 mmol) as a beige crystalline solid (387 mg, 81%): mp 178-179° C.; 1H NMR (DMSO-d6) 0.93 (d, J=5.1, 2H), 1.05-1.70 (m, 17H), 1.85-2.07 (m, 5H), 2.56 (t, J=6.0, 2H), 2.72-2.88 (m, 2H), 3.90 (t, J=6.0, 2H), 6.63 (d, J=9.0, 2H), 6.71 (d, J=9.0, 2H), 8.88 (bs, 1H); Anal. calcd for C24H35NO2: C, 78.00; H, 9.55; N, 3.79. Found: C, 78.03; H, 9.44; N, 3.77.
Reaction SMILES: Cl[C:2](=[C:5]1[C:10](=O)[CH2:9][C@H:8]2[C@@H:6]1[C:7]2([CH3:13])[CH3:12])[CH2:3][CH3:4].C([O:16][C:17](=[O:20])[CH2:18][SH:19])C>C1COCC1.C(O)C.CC(=O)OCC>[CH2:3]([C:2]1[S:19][C:18]([C:17]([OH:20])=[O:16])=[C:10]2[C:5]=1[CH:6]1[C:7]([CH3:13])([CH3:12])[CH:8]1[CH2:9]2)[CH3:4]
Reactant: CCC(Cl)=C1C(=O)C[C@H]2[C@@H]1C2(C)C
Reactant: CCOC(=O)CS
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1sc(C(=O)O)c2c1C1C(C2)C1(C)C
Temperature: 30 °C
Reaction time: 2 h
Yield: 27.5 %

Procedure:
To a solution of (1R,5S)-2-[1-chloro-propylidene]-6,6-dimethyl-bicyclo[3.1.0]hexan-3-one (11.0 g, 55.4 mmol) in THF (40 mL) a solution of ethyl-2-mercaptoacetate (9.6 mL, 87.2 mmol) in a freshly prepared solution of Na (3.9 g, 170 mmol) in ethanol (95 mL) is added at 30° C. The reaction mixture is stirred at 30° C. for 2 h before it is diluted with EA and washed with 1 N aq. NaOH and brine. The organic extracts are dried over Na2SO4 and the solvent is removed in vacuo. The resulting brown oil (9.66 g) is dissolved in ethanol (365 mL) and diluted with 1 N aq. LiOH (365 mL). The mixture is refluxed for 1 h before the organic solvent is removed in vacuo. Solid material is filtered off and the filtrate is extracted twice with diethyl ether. The organic layer is extracted back with 1 N aq. LiOH and brine. The aq. extracts are acidified with aq. HCl (37%). The precipitate that formes is collected, washed with water followed by hexane, and dried under high vacuum to give rac-(1aS,5aR)-2-ethyl-1,1-dimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (3.6 g) as beige crystals. From the hexane washings a second crop (2.37 g) is obtained after evaporation of the solvent; LC-MS: tR=0.99 min, [M+1]+=237.24, 1H NMR (CDCl3): δ 3.00 (dd, J=5.9, 19.3 Hz, 1H), 2.84-2.70 (m, 3H), 1.92-1.86 (m, 2H), 1.28 (t, J=7.0 Hz, 3H), 1.12 (s, 3H), 0.70 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].I[CH:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH:11]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6])([CH3:13])[CH3:12]
Reactant: OCc1cccc(O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc(CO)c1
Temperature: 85 °C
Yield: 123.4 %

Procedure:
A mixture of 3-hydroxybenzyl alcohol (2.00 g, 0.014 mol), 2-iodopropane (2.4 ml, 8.29 mmol), cesium carbonate (8.00 g, 0.0246 mol) in DMF (10 ml) was heated at 85° C. for 8 h. The reaction was diluted with water (100 ml) and extracted with DCM (30 ml) and this was washed with water (2×30 ml). The product was chromatographed on silica using DCM:methanol (19:1) to afford 3-isopropoxybenzyl alcohol (1.70 g, 73%) as an orange liquid.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[C:16]2[CH2:15][CH2:14][CH:13](Br)[C:12](=O)[C:11]=2[CH:10]=[CH:9][CH:8]=1)C.[C:20]1([CH:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27]([NH2:29])=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([CH:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27]2[S:28][C:13]3[CH2:14][CH2:15][C:16]4[C:11](=[CH:10][CH:9]=[CH:8][C:7]=4[O:6][CH2:5][C:4]([OH:3])=[O:19])[C:12]=3[N:29]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: NC(=S)C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1cccc2c1CCC(Br)C2=O
Product: O=C(O)COc1cccc2c1CCc1sc(C(c3ccccc3)c3ccccc3)nc1-2
Yield: 31 %

Procedure:
Using ethyl[(6-bromo-5,6,7,8-tetrahydro-5-oxo-1-naphthalenyl)oxy]acetate and diphenylthioacetamide, the procedure of Example 52 was otherwise repeated to synthesize the title compound. Yield 31%. Amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[C:16]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[C:11]([CH3:12])=[N:10][O:9][N:8]=1)=[O:5].[CH2:25](Br)[CH:26]=[CH2:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:27]([N:6]([C:7]1[C:11]([CH3:12])=[N:10][O:9][N:8]=1)[C:4](=[O:5])[C:3]1[CH:13]=[CH:14][C:15]([C:21]([F:24])([F:23])[F:22])=[C:16]([S:17]([CH3:20])(=[O:19])=[O:18])[C:2]=1[CH3:1])[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: Cc1nonc1NC(=O)c1ccc(C(F)(F)F)c(S(C)(=O)=O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN(C(=O)c1ccc(C(F)(F)F)c(S(C)(=O)=O)c1C)c1nonc1C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
150 mg (0.413 mmol) of 2-methyl-N-(4-methyl-1,2,5-oxadiazol-3-yl)-3-(methylsulfonyl)-4-(trifluoromethyl)benzamide and 50 mg (0.413 mmol) of allyl bromide are dissolved in 5 ml of N,N-dimethylformamide, and 0.057 mg (0.413 mmol) of potassium carbonate is added. The reaction mixture is stirred at 80° C. for 8 h and taken up in 5 ml of water and extracted twice with 10 ml each time of dichloromethane. The organic phase is dried over Na2SO4 and concentrated. The residue is purified by means of preparative HPLC (acetonitrile, water). Yield 160 mg (86%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]12[CH2:11][CH2:10][C:9]([NH:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([CH2:8][CH2:7]1)[CH2:14][C:13]2=[O:15])=[O:5])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C1(C(C)=O)CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C12CCC(NCc3ccccc3)(CC1)CC2=O
Temperature: 25 °C

Procedure:
Toluene (100 mL) was added to 1-acetyl-4-oxocyclohexyl carboxylic acid ethyl ester (8.0 g, 38 mmol) and then the resulting mixture was stirred. To the mixture, there were added benzylamine (5.3 mL, 49 mmol) and p-toluenesulfonic acid monohydrate (76 mg, 0.40 mmol). The mixture was refluxed for 8 hours with a Dean-Stark apparatus under the dehydration conditions. After cooled to room temperature, the mixture was concentrated under reduced pressure to give a crude product. The resulting crude product was treated according to the silica gel column chromatography (eluting solution: hexane/ethyl acetate) to thus obtain a mixture of the desired product and an imine derivative thereof. The mixture was dissolved in chloroform (200 mL) and then the resulting solution was treated with a 0.5 mol/L hydrochloric acid solution (100 mL). The suspended organic phase was separated, then treated with a 5% aqueous solution of sodium hydrogen carbonate and then separated. The organic phase was dried over anhydrous magnesium sulfate, followed by the removal of the drying agent through filtration and the subsequent concentration of the resulting filtrate under reduced pressure to thus give the desired product as a white solid. (2.9 g; yield: 26%).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([OH:11])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.[Cl:19]CCl>C1COCC1>[Cl:19][C:4]1[N:3]=[CH:2][C:7]([CH2:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[O:11])=[CH:6][CH:5]=1
Reactant: Nc1ccccn1
Reactant: ClCCl
Reactant: O=C(O)Cc1cccnc1Cl
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)nc1)Nc1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
Under inert atmosphere, 6.2 g (38.5 mmol) of N,N-carbodiimidazole is added to a suspension of 6 g (35 mmol) of 2-chloropyridylacetic acid in anhydrous THF (90 ml) at room temperature. The reaction mixture is stirred at this temperature for 2 hours, then 5.4 g (57.7 mmol) of 2-aminopyridine is added and the mixture is heated for 2 hours under reflux. 200 ml of dichloromethane is added to the reaction mixture, cooled beforehand to room temperature, the organic phase thus obtained is washed with a saturated solution of ammonium chloride, then with an aqueous solution of soda (1N), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography (eluent: A/B=dichloromethane/ethyl acetate 0% to 70% of B). 5.6 g of compound is obtained in the form of a white powder. Yield 65%. Melting point: 130° C. MH+: 248 (Tr: 5.6 min, condition 1).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:6]=1)([F:4])[CH3:3].[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[O:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44]>>[F:4][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:44][C:43]2[CH:45]=[CH:46][CH:47]=[C:41]([O:40][C:31]3[C:30]4[C:35](=[CH:36][C:37]([O:38][CH3:39])=[C:28]([O:27][CH3:26])[CH:29]=4)[N:34]=[CH:33][N:32]=3)[CH:42]=2)=[O:19])[N:7]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1cc(NC(=O)Oc2ccccc2)n(-c2cccnc2)n1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(F)F)nn4-c4cccnc4)c3)c2cc1OC
Yield: 62.8 %

Procedure:
Following the procedure in Example 115C, phenyl 3-(1,1-difluoroethyl)-1-(pyridin-3-yl)-1H-pyrazol-5-ylcarbamate (27 mg, 0.078 mmol) was treated with 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (26 mg, 0.086 mmol) (prepared as described in Example 113A) to afford 1-(3-(1,1-difluoroethyl)-1-(pyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (27 mg, 0.049 mmol, 63%). 1H NMR (300 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.82-8.78 (m, 2H), 8.70 (d, 1H), 8.54 (s, 1H), 8.04 (d, 1H), 7.65-7.61 (m, 2H), 7.54-7.51 (m, 2H), 7.19 (d, 1H), 6.93 (d, 1H), 6.69 (s, 1H), 3.99 (s, 6H), 2.00 (t, 3H); LC-MS (ESI) m/z 548 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:23][C:24]2[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC([Cl:53])=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[Cl-].ClC1C=CC=CC=1C[Zn+]>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:53])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: Clc1ccccc1C[Zn+]
Agent: [Cl-]
Product: Clc1ccccc1Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Yield: 38 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-[(4-fluorophenyl)methyl]pyridazine (Intermediate 51) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and (2-chlorobenzyl)zinc(II) chloride in 38% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[CH3:13].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[N:18]=[CH:17][C:16]=1[NH2:22].N1C=CC=CC=1>ClCCl>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[N:18]=[CH:17][C:16]=1[NH:22][C:7](=[O:8])[C:6]1[CH:10]=[C:11]([CH3:12])[C:3]([O:2][CH3:1])=[C:4]([CH3:13])[CH:5]=1
Reactant: COc1c(C)cc(C(=O)Cl)cc1C
Reactant: Nc1cnc(Cl)cc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(C)cc(C(=O)Nc2cnc(Cl)cc2Cl)cc1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
With ice cooling, 1.20 g of 4-methoxy-3,5-dimethylbenzoyl chloride, dissolved in 1 ml of dry dichloromethane were initially added dropwise to a solution of 0.82 g of 4,6-dichloropyridin-3-ylamine in 8 ml of dry dichloromethane. A solution of 0.4 ml of absolute pyridine in 1 ml of dry dichloromethane was then added, and the reaction was stirred at 0° C. for 2 h, the product partially precipitating slowly. Approx. 10 ml of 10% strength aqueous sodium bisulfate solution were then added, and the mixture was stirred for five minutes. The aqueous phase was then decanted off and the solid-containing organic phase was concentrated under reduced pressure and freeze-dried. This gave 1.63 g (100%) of the product, which was used for the next step without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[CH:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)([CH3:23])[CH3:22]>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([CH:21]([CH3:23])[CH3:22])[CH:29]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: CC(C)c1cccc(B(O)O)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3cccc(C(C)C)c3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 3-isopropyl-phenylboronic acid (53 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH:1]1([C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:8])[C:6]#C)[CH2:4][CH2:3][CH2:2]1.[Mn]([O-])(=O)(=O)=[O:16].[K+].S([O-])([O-])=O.[Na+].[Na+].[OH2:27]>>[CH:1]1([C:5]([OH:8])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([OH:16])=[O:27])[CH2:4][CH2:3][CH2:2]1
Reactant: C#CC(O)(c1ccccc1)C1CCC1
Reactant: O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: O=C(O)C(O)(c1ccccc1)C1CCC1
Yield: 36.8 %

Procedure:
To 1-cyclobutyl-1-phenyl-2-propin-1-ol (Compound (10), 5.80 g), water (20 ml) was added. Under stirring, an aqueous solution (300 ml) of potassium permanganate (14.0 g) was added dropwise to the resulting mixture at 0° C., followed by vigorous stirring for further 2 hours. Sodium sulfite was added to the reaction mixture at room temperature. The precipitate so obtained was filtered through Celite and the filtrate was extracted with ether. The organic layer was dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain the title compound (2.36 g, 36.8%)) as colorless prism.
Reaction SMILES: O([C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]=1[N+:19]([O-:21])=[O:20])S(C(F)(F)F)(=O)=O.[NH2:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH:26]=[CH:27][CH:28]=1>>[N+:19]([C:10]1[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=2[CH:17]=[CH:18][C:9]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:36])[CH:24]=1)([O-:21])=[O:20]
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2c1CCCC2
Product: CC(C)(C)OC(=O)Nc1cccc(Nc2ccc3c(c2[N+](=O)[O-])CCCC3)c1

Procedure:
1-Nitro-5,6,7,8-tetrahydronaphthalen-2-yl triflate and tert-butyl 3-aminophenylcarbamate were used in a process similar to Example 1(1) to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:3]=1[C:4]([NH2:6])=O.P(Cl)(Cl)(Cl)=O.O>C1C=CC=CC=1>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([C:12]([F:15])([F:13])[F:14])[C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1c(C(F)(F)F)ccc(Cl)c1Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Product: N#Cc1c(C(F)(F)F)ccc(Cl)c1Cl
Temperature: 35 °C
Yield: 95.8 %

Procedure:
To a solution of 229 g of 2,3-dichloro-6-trifluoromethylbenzamide in 2 liters of benzene was added 409 g of phosphorus oxychloride and then the mixture was heated at ref lux for 3.5 hours. After cooling, the solution was gradually added into 2 liters of water maintained at 30-40° C. to hydrolyze the excess phosphorus oxychloride therein and was allowed to separation. The aqueous layer was extracted with benzene, and the extract was combined with the organic layer previously obtained, washed with water and with saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure, and the crude product obtained was washed with n-hexane and filtered to obtain 204 g of the title compound(mp. 53-54° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH:7]([N:10]1[CH:19](NC(C(OC(C)(C)C)=O)CC)[CH2:18][C:17]2[C:12](=[CH:13][C:14]([Cl:31])=[CH:15][CH:16]=2)[C:11]1=[O:32])[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].Cl>C(O)(C)C.C(OCC)(=O)C.O>[Cl:31][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[CH:19][N:10]([C@@H:7]([CH2:8][CH3:9])[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:33])[C:11]2=[O:32])=[CH:16][CH:15]=1
Reactant: CCC(NC1Cc2ccc(Cl)cc2C(=O)N1C(CC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)O
Product: CC[C@@H](C(=O)OC(C)(C)C)n1ccc2ccc(Cl)cc2c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-[3-(1-tertbutoxycarbonyl-propylamino)-7-chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-butyric acid tert-butyl ester (8.58 g) in isopropanol (180 ml) at 0° C. was added concentrated hydrochloric acid (20 ml). The resulting mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was then diluted with ethyl acetate (500 ml) and water (150 ml). The organic phase was separated and washed with water, then brine, dried (magnesium sulfate), filtered and concentrated. The sub-title product was obtained as a yellow solid (5.57 g, 97%). m.p. 111.3-111.8° C.; [α]25D-52.30 (c=1, CHCl3); IR (solid) 1731.4, 1649.5, 1593.2, 1229.6, 1152.8, 901.9 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.95 (3H, t), 1.48 (9H, s), 1.95 (1H, m), 2.30 (1H, m), 5.55 (1H, m), 6.40 (1H, m), 7.15 (1H, m), 7.49 (1H, m), 7.61 (1H, m), 8.40 (1H, m) ppm; 13C NMR (100 MHz, CDCl3) δ 10.9, 24.8, 28.1, 59.2, 82.8, 105.7, 127.3, 127.8, 128.1, 129.5, 133.1, 133.2, 135.4, 161.8, 170.2; MS ES(+) 322.4 (M+H).
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:59][C:60]1[CH:61]=[C:62](B(O)O)[CH:63]=[CH:64][C:65]=1[O:66][CH3:67]>>[F:59][C:60]1[CH:61]=[C:62]([C:2]2[C:3](=[O:32])[C:4]3[C:9]([C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:26][CH2:27]2)[CH:5]=3)[CH:63]=[CH:64][C:65]=1[O:66][CH3:67]
Reactant: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2ccc(F)cc2F)CC1
Reactant: COc1ccc(B(O)O)cc1F
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc(C2=C(c3ccc(F)cc3F)c3ccc(OCCN4CCN(S(C)(=O)=O)CC4)cc3C2=O)cc1F
Yield: 68 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-{2-[4-(methylsulfonyl)piperazin-1-yl]ethoxy}-1H-inden-1-one obtained in Step 1 of Example 116 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one and 3-fluoro-4-methoxyphenylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (68%).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=1.O>C(Cl)Cl.CCN(CC)CC>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[N:13][CH:14]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Br)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
Pivaloyl chloride (85 mL, 0.69 mol) was added to a solution of 5-bromopyridin-2-amine (100 g, 0.58 mol) and Et3N (120 mL, 0.87 mmol.) in CH2Cl2 at −78° C. The temperature was allowed to warm to room temperature and the stirring was continued overnight. The reaction mixture was poured into water, extracted with CH2Cl2, dried over MgSO4, evaporated in vacuo and purified by chromatography on silica gel (10% EtOAc in petroleum ether) to afford N-(5-bromopyridin-2-yl)pivalamide (130 g, 87% yield). 1H NMR (CDCl3, 400 MHz) δ 8.28 (d, J=2.0 Hz, 1H), 8.17 (d, J=9.2 Hz, 1H), 7.99 (br s, 1H), 7.77 (dd, J=9.2 and 2.0, 1H), 1.28 (s, 9H).
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].O[C@@H:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][C:14]2[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)[N:9]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].O[C@H]1CC[C@H](CC2C=NC(C(F)(F)F)=CC=2)N1C(OC(C)(C)C)=O>CO.O>[F:22][C:20]([F:23])([F:21])[C:17]1[N:16]=[CH:15][C:14]([CH2:13][C@H:10]([NH:9][C:24](=[O:25])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:11][CH2:12][C:8]#[CH:1])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(C(F)(F)F)nc2)CC[C@H]1O
Reactant: O=C([O-])[O-]
Agent: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(C(F)(F)F)nc2)CC[C@@H]1O
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#CCC[C@H](Cc1ccc(C(F)(F)F)nc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dimethyl 1-diazo-2-oxopropyl phosphonate (505 mg, 2627 μmol) (commercially available from TCI America Organic Chemicals Product List (Order Number D3546)), followed by K2CO3 (545 mg, 3941 μmol) was added to a diastereomeric mixture of (2R,5R)-tert-butyl 2-hydroxy-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrrolidine-1-carboxylate and (2S,5R)-tert-butyl 2-hydroxy-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrrolidine-1-carboxylate (455 mg, 1314 μmol) in MeOH (1.3 mL) at room temperature. The mixture was stirred at room temperature for 4 hours, diluted with H2O (15 mL), and extracted with DCM (3×20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting yellow solid was dissolved in MeOH/DCM, absorbed onto silica gel, and purified by flash chromatography (silica gel, 10% to 30% EtOAc/hexanes) to deliver (R)-tert-butyl 1-(6-(trifluoromethyl)pyridin-3-yl)hex-5-yn-2-ylcarbamate (284 mg, 63%) as an off-white solid. LCMS (API-ES) m/z: 343.1 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:9][C:8]([C:10]2[C:11]3[CH:23]=[CH:22][Se:21][C:12]=3[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1)=O.C(OCC)(=O)C.CCCCCC>O>[OH:2][CH2:3][C:5]1[O:9][C:8]([C:10]2[C:11]3[CH:23]=[CH:22][Se:21][C:12]=3[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(-c2nn(-c3ccccc3)c3[se]ccc23)o1
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: OCc1ccc(-c2nn(-c3ccccc3)c3[se]ccc23)o1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
1.98 g (0.018 mole) of granular anhydrous calcium chloride, 1.377 g (0.036 mole) of sodium brorhydride and 100 ml of anhydrous THF were reacted at room temperature for 4 h to form a white dispersion of calcium borohydride (Ca(BH4)2). To the dispersion compound 78 (0.744 g, 0.002 mole) was added and was reduced by heating under refluxing for 24 h. The progress of the reduction reaction was monitored by TLC with ethyl acetate (EA):n-hexane=3:2. When the reaction was completed, the reaction mixture was cooled to room temperature, and THF was evaporated under a reduced pressure. The remaining reaction mixture was poured into water to stop the reaction, and then was extracted with chloroform. The organic layer was recovered, dried over MgSO4 and filtered. The solvent of the filtrate was evaporated under a reduced pressure, and the residue was subjected to a column chromatography with EA:n-hexane=3:2, and then recrystallized from EA to afford compound 80 in white crystals (0.612 g). Yield: 88.9%;